Differentiation of naive, uncommitted Th precursor cells into Th1 or Th2 cells is a complex developmental process and understanding the underlying molecular mechanisms may provide a conceptual framework in developing immune modulation therapies against allograft rejection, autoimmune and allergic diseases. The dominant factors that control Th cell differentiation program are now recognized to derive from signals activated by IL-12 or IL-4 cytokines. In on-going studies we found that SOCS proteins are potent feed-back regulators of IL-12/STAT4 and IL-4/STAT6 signaling, two antagonistic and critical pathways implicated in lymphocyte development. We have also found that three members of the SOCS family are differentially expressed in differentiated Th cells. Th1 cells predominantly express SOCS1 and SOCS2 but synthesize minute amounts of SOCS3 mRNAs or protein. Conversely, Th2 cells express 23-fold higher levels of SOCS3 than Th1 cells. In the up-coming fiscal year we intend to investigate whether mutually exclusive utilization of STAT4 and STAT6 signaling pathways by Th cells derives from SOCS3- or SOCS1-mediated repression of IL-12/STAT4- or IL-4/STAT6-signaling in Th2 and Th1 cells, respectively. We also intend to investigate whether we can change the pattern of cytokine expression of Th1 and Th2 cells by forced over-expression of SOCS3 or SOCS1 respectively. To this end, we have constructed retroviral vectors expressing SOCS1, SOCS2 and SOCS3. Vectors expressing anti-sense SOCS1, SOCS2, SOCS have also been constructed for use in depleting the various SOCS proteins in Th1 or Th2 cells. These studies are of interest not merely in the context of Th differentiation, but also because SOCS1 and SOCS3 proteins can serve as potential therapeutic targets for immune modulation therapy. Our ultimate aim is to test these constructs for ex-vivo treatment of uveitis.